Abstract Mirna Analytics is proposing to develop a microRNA (miRNA) marker for pulmonary hypertension. This proposal is focused on the identification of optimal miRNA's to form composite markers that can be measured in the serum/plasma. Pulmonary hypertension, an excessive increase of the pressure in the pulmonary circulation, can be due to many different reasons. Pulmonary hypertension can be a deadly disease and in all cases confers a worse prognosis. Aside from genetic testing and the measurement of the right-heart stress marker B-type natriuretic peptide, biomarkers that would identify the molecular or cellular pathobiologic mechanism that identify the cause of pulmonary hypertension are not established. Mirna Analytics is focusing on miRNAs as novel candidate biomarkers because these molecules are stable in serum and plasma samples and are circulating for short- and long-distance communication between cells. A biomarker tool that can identify the pathogenesis that causes pulmonary hypertension would significantly improve disease management by facilitating personalized therapy. Preliminary studies were conducted with plasma and serum samples that were bio-banked from previously conducted studies and de-identified by two different pulmonary hypertension centers at the Universities of Heidelberg and Zurich. The studies were focused on the effects of supervised exercise, or nightly oxygen interventions, respectively. We identified miRNA-based markers that changed with the intervention and that were correlated with the 6-minute walking distance at baseline. Based on these preliminary data, proposed study is designed to test the Phase I Hypothesis: A microRNA marker from the serum/plasma is predictive of clinical improvement in pulmonary hypertension following therapeutic management with exercise, or nightly oxygen, and has some overlap with predictors of improvements following therapy with the breathing stabilizer, Acetazolamide. Specific Aim 1 is to test our two miRNA markers identified in preliminary studies (miR-22-3p relative to miR-451a) or (miR-22-3p + miR-21-5p relative to spike-RNA + miR-451a), respectively on validation sample cohorts from Acetazolamide-treated patients from the University of Zurich and a new cohort of 30 paired samples from the exercise intervention study at the University of Heidelberg. Specific Aim 2 is to expand our miRNA marker portfolio by testing additional 25 miRNA species. Specific Aim 3 is to test the RNA from 20 randomly selected pairs each from the sample cohorts from: a) oxygen, or placebo group patients from the University of Zurich; and b) before and after exercise intervention study at the University of Heidelberg with an Omics-tool to further develop our miRNA marker. The Commercial Application is to develop a circulating biomarker that supports the $3.3 billion PH therapeutic market.